Hyperthermic intraperitoneal chemotherapy in colorectal cancer

Abstract Background This study evaluated the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer with peritoneal metastases (pmCRC) in a large international data set of patients. Patients and Methods Patients with pmCRC from 39 centres who underwent cytoreductive surgery with HIPEC between 1991 and 2018 were selected and compared for the HIPEC protocols received—oxaliplatin-HIPEC versus mitomycin-HIPEC. Following analysis of crude data, propensity-score matching (PSM) and Cox-proportional hazard modelling were performed. Outcomes of interest were overall survival (OS), recurrence-free survival (RFS) and the HIPEC dose–response effects (high versus low dose, dose intensification and double drug protocols) on OS, RFS and 90-day morbidity. Furthermore, the impact of the treatment time period was assessed. Results Of 2760 patients, 2093 patients were included. Median OS was 43 months (95% c.i. 41 to 46 months) with a median RFS of 12 months (95% c.i. 12 to 13 months). The oxaliplatin-HIPEC group had an OS of 47 months (95% c.i. 42 to 53 months) versus 39 months (95% c.i. 36 to 43 months) in the mitomycin-HIPEC group (P = 0.002), aHR 0.77, 95% c.i. 0.67 to 0.90, P < 0.001. The OS benefit persisted after PSM of the oxaliplatin-HIPEC group and mitomycin-HIPEC group (48 months (95% c.i. 42 to 59 months) versus 40 months (95% c.i. 37 to 44 months)), P < 0.001, aHR 0.78 (95% c.i. 0.65 to 0.94), P = 0.009. Similarly, matched RFS was significantly higher for oxaliplatin-HIPEC versus others (13 months (95% c.i. 12 to 15 months) versus 11 months (95% c.i. 10 to 12 months, P = 0.02)). High-dose mitomycin-HIPEC protocols had similar OS compared to oxaliplatin-HIPEC. HIPEC dose intensification within each protocol resulted in improved survival. Oxaliplatin + irinotecan-HIPEC resulted in the most improved OS (61 months (95% c.i. 51 to 101 months)). Ninety-day mortality in both crude and PSM analysis was worse for mitomycin-HIPEC. There was no change in treatment effect depending on the analysed time period. Conclusions Oxaliplatin-based HIPEC provided better outcomes compared to mitomycin-based HIPEC. High-dose mitomycin-HIPEC was similar to oxaliplatin-HIPEC. The 90-day mortality difference favours the oxaliplatin-HIPEC group. A trend for dose–response between low- and high-dose HIPEC was reported.


Introduction
Colorectal cancer is the third most frequent malignancy in men and women and the second highest cause of cancer-related mortality worldwide 1 .Peritoneal metastases are detected in approximately 30% of patients with metastatic or recurrent disease 2 .Cytoreductive surgery (CRS) and the intraoperative instillation of hyperthermic intraperitoneal chemotherapy (HIPEC) has resulted in median overall survival (OS) times of up to 41 months in randomized trials and prospective series from expert centres 3 , which compares favourably to the median of 16 months for systemic therapy alone 2 .The recently reported UNICANCER phase III trial of oxaliplatin-HIPEC (Ox-HIPEC) for peritoneal metastasized colorectal cancer (pmCRC; PRODIGE 7)  determined that there was no added survival benefit when adding HIPEC to CRS, while the 60-day complication rate was higher 3 .Equally, there exists no consensus as to which HIPEC agent should be utilized for these patients as there are a number of different protocols available 4 .
Since the reporting of the RCT on cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with pmCRC 5 , many centres have utilized a mitomycin C (MMC-) HIPEC protocol; however, following additional reports [6][7][8] , others have adopted Ox-HIPEC.After publication of results from the PRODIGE 7 trial 9 , which applied Ox-HIPEC but failed to identify a significant survival effect, many centres have changed to MMC-HIPEC.However, currently there are significant debates concerning HIPEC use in colorectal cancer 10 .
The aim of this study was to evaluate the efficacy of HIPEC in colorectal cancer in a large international data set of patients in relation to overall and recurrence-free survival, HIPEC intensity effects and morbidity.

Databases and study population
The MitOxHIPEC study (Mitomycin C versus Oxaliplatin Hyperthermic Intraperitoneal Chemotherapy combined with Cytoreductive Surgery for the Treatment of Colorectal Cancer with Peritoneal Metastases) was a retrospective, multi-institutional cohort study investigating the management of patients who underwent CRS/HIPEC for the treatment of pmCRC.Data were compiled across eight countries and 39 treatment centres that were part of the Peritoneal Surface Oncology Group International (PSOGI), Nordic Peritoneal Oncology Group (NPOG), American Society for Peritoneal Surface Malignancy (ASPSM) and BIG-RENAPE Groups.Data were identified from the prospectively maintained databases of the collaborative groups and compiled in a central, standardized, de-identified and password-protected database.During inputting of data into the central database, data were checked for accuracy and completeness with potential duplicate values removed by cross-referencing patients by country and treatment centre, patient age, gender, date of CRS and corresponding intraoperative peritoneal cancer indexes (PCIs).Attempts to rectify missing or inconsistent data were made by e-mail exchanges with referral centres where possible.To ensure concordance between databases and data integrity, final data capture was audited by two of the investigators prior to analysis (Fig. 1).All data were collected in accordance with each institution's guidelines for retrospective studies.The retrospective capture of data for this study was approved by each centre's or national registry's respective ethical review boards.

Surgical procedures and utilized HIPEC protocols
The study included patients who underwent complete cytoreduction with HIPEC with either MMC-or oxaliplatin-based treatment protocols for the treatment of patients with pmCRC between 1991 and 2018.The extent of peritoneal deposits was calculated according to the PCI.CRS included the resection of the primary tumour in the context of synchronous metastatic disease with greater omentectomy, and resection of all peritoneal deposits by combining peritonectomy procedures and resections of involved organs where necessary.Completeness of cytoreduction (CC) was evaluated using the CC score 11 .The present study excluded patients who did not have complete data on their CC score or if they had macroscopic residual disease >2.5 cm (CC-3) and all analyses were adjusted for remaining CC score subgroups.HIPEC was delivered at the end of surgical procedures with protocols varying according to the institution, and HIPEC being performed using open or closed techniques, depending on unit preference.Details regarding utilized HIPEC protocols are provided in Supplementary Methods S1.

Study outcomes
The primary outcome of the study was patient OS defined as time from CRS/HIPEC to date of last follow-up with death from any cause.Only patients with complete data were included in the survival analyses.Secondary outcomes included patient recurrence-free survival (RFS), with RFS defined as time from CRS to recurrence at any site or death, whichever occurred first.Survival subgroup analyses included 1-, 3-and 5-year survival rates, the impact of varying HIPEC protocols including dosages on OS/RFS as well as the impact of treatment time periods on primary endpoints.Details regarding HIPEC protocols and resulting stratifications are provided in the Supplementary Methods.
Further secondary outcomes included the recurrence site, in-hospital and 90-day postoperative morbidity, defined using the Clavien-Dindo classification 12 .

Data and statistical analyses
Patient characteristics were reported using frequency and descriptive analyses.Comparison of normally distributed variables was performed using Student's t test and ANOVA.Non-normally distributed data were analysed using the Kruskal-Wallis test.Categorical variables were analysed using the chi-square test if suspected 2 × 2 table cell counts were >5 and/or not more than 20% of cell counts were <5.If this assumption was not met, then the Fisher's exact test was used.
To correct for potential treatment allocation bias and confounding factors between treatment groups, propensity score matching (PSM) was performed to control for patient baseline characteristics.In a first step, unmatched patient demographics were cross-tabulated and inspected for pre-existing imbalances of preoperative factors that may have impacted the allocation to a particular HIPEC treatment arm.Subsequently, a propensity score was calculated for each patient as the predicted probability of the allocation to Ox-HIPEC using multivariable logistic regression, which included pre-and intraoperative factors identified from the first crude group comparison supplemented by the addition of factors that may impact patient prognosis including age, gender, ASA category, the presence of positive lymph nodes, the presence of liver metastases at the time of CRS/HIPEC, PCI, CC scores and the use of preoperative systemic chemotherapy.As complete propensity scores cannot be calculated in the presence of missing data for any of the included predicting variables, missing data were computed as such to allow for the lowest attrition rate of study subjects during matching steps.Matching occurred at a 1:1 ratio with no reuse of study subjects using a nearest-neighbour method, and treatment and control units were matched in a random order to ensure optimal distribution of propensity scores.Covariate balance following matching procedures was assessed with Love plots determining mean differences and the difference in cumulative density between groups using the Kolmogorov-Smirnov tests 13 .
Methodological details are provided in Supplementary Methods.Overall survival and RFS times were plotted stratified according to the utilized HIPEC drug and associated dose-intensification protocols using the Kaplan-Meier method and resulting survival times compared using the log-rank test.This was first done by analysing crude (unmatched) survival rates and subsequently the matched cohorts.Uni-and multivariable Cox regression analysis was performed to assess the prognostic impact of HIPEC for both OS and RFS.The proportional hazards assumption was checked for all variables using scaled Schoenfeld residuals and by inspecting the resulting time-dependent plots.Multivariable analyses were adjusted for factors (age, gender, positive lymph node status in the primary tumour, synchronous versus metachronous disease, colonic versus rectal primaries, the presence of liver metastases, preoperative systemic chemotherapy, PCI, CC score, HIPEC agent used, HIPEC intensity protocol used, postoperative complications, the use of adjuvant chemotherapy) known to influence the prognosis of CRC patients undergoing CRS/ HIPEC and were performed in the crude and matched cohorts.The crude data analysis included the computation of results for missing variables to assess their possible impact on outcomes.For matched data, no missing variables were present as this is a result of the matching process itself.Resulting data are reported as HR with associated 95% c.i.All statistical analyses were performed using R Statistical Packages and all P < 0.05 were considered statistically significant.

Patient characteristics
In total, 2760 individual patients contributed to the original database.After application of selection criteria, 2093 study subjects remained, of whom 849 had MMC-HIPEC and 1244 had Ox-HIPEC (Fig. 1).A summary of patients' baseline characteristics and differences between groups is provided in Table S1.Following PSM, 1324 patients were successfully matched (662 patients in the MMC-HIPEC and 662 patients in the Ox-HIPEC treatment group).Matching resulted in excellent covariate balance and correction of differences in underlying patient characteristics (Fig. S1).The mean number of patients per centre contributing to the unmatched cohort was 32 (s.d.52.9) and matched cohort 60 (s.d.92.8), respectively.The mean number of patients per centre per year (according to the number of years that the said centre has been included) was 10.4.An overview of matched patient characteristics is provided in Table 1.

Long-term survival outcomes
Of the 2093 patients included in the analysis, 931 (44.5%) died during follow-up and 1759 had complete data on recurrences.Of these, 1257 (71.5%) recurred during follow-up.Median OS was 43 months (95% c.i. 41 to 46 months) with a median RFS of 12 months (95% c.i. 12 to 13 months).

In-hospital morbidity and 90-day mortality
Major postoperative morbidity did not differ between MMC-HIPEC and Ox-HIPEC in the matched cohort, but it did differ in the unmatched cohort by only 3% (Table 1 and Table S1).Ninety-day mortality differed in both the matched (MMC-HIPEC 7.9% versus Ox-HIPEC 4.2%, P = 0.008) and unmatched cohorts (MMC-HIPEC 9.0% versus Ox-HIPEC 5.7%, P = 0.004), Table 1 and Table S1.Morbidity and mortality in relation to dose-intensification or second chemotherapeutic drug are reported in Table S3.

Impact of treatment time period
A total of 61.8% of the patients in this study were treated in the most recent time period of 2012-2018, with no difference between the groups in terms of proportion treated in this time period-Ox-HIPEC 60.7% versus MMC-HIPEC 62.8% (

Fisher et al. | 7
Single-agent low-dose HIPEC was ineffective, but a significant step-wise increase in RFS was observed from low-dose to high-dose to double-agent HIPEC.The observed RFS of 10 months in the low-dose group was similar to the no HIPEC group in the PRODIGE 7 trial (11 months), indicating low doses may not provide any benefit 9 .The RFS increase to 12 and 13 months for the HIPEC intensification groups correlated with the high-dose regimen in PRODIGE 7, but the trial was not powered to show small RFS benefits.The present analysis of over 2000 patients showed a potential RFS benefit with a hazard ratio of 0.84, similar to the benefit seen in PRODIGE 7 (HR 0.90).The focus on RFS instead of OS is because OS is dependent on additional treatments.The congruence between the two studies suggests HIPEC may convey a small but clinically relevant RFS benefit, which likely contributes to the subsequent significant OS benefit seen in the present analysis.
The world primarily uses either oxaliplatin or mitomycin for HIPEC in colorectal cancer 13 .The present study showed that switching from Ox-HIPEC to MMC-HIPEC does not provide any added benefit and may result in added 90-day mortality.The PRODIGE 7 trial used high-dose oxaliplatin HIPEC, but due to the lack of a clear benefit, some institutions switched to MMC-HIPEC.Effect estimates for other variables of interest must be interpreted with caution, due to the risk of so-called 'Table 2 fallacy' 14 .
This study suggests the switch is unnecessary.The study found that low-dose MMC-HIPEC (<25 mg/m 2 ) may result in worse outcomes than high-dose MMC-HIPEC (>25 mg/m 2 ), which achieved similar outcomes to oxaliplatin-based therapies.This is the first study to demonstrate a clear RFS benefit with the high-dose regimen.If a switch has been made, it is advisable to use a high-dose MMC-HIPEC regimen instead of a low-dose regimen, based on a previous preclinical chemosensitivity study 3 .
a  In a comprehensive review 15 , it was found that 60 HIPEC protocols for pmCRC have been published in 25 years with variations also documented by other systematic reviews 4,16,17 .The present analysis found higher-dose and dual-agent protocols improved OS, particularly if Ox-HIPEC was used.The present study identified oxaliplatin + irinotecan HIPEC as a promising regimen for future trials with a median OS of 61 months and RFS of 15 months-a protocol that has been studied previously with   15,16 .However, the pronounced survival differences justify a prospective RCT with a reasonable sample size.A randomized trial using this protocol currently underway in Sweden with the aim of starting patient recruitment in 2021 18 .
Two previous cohort studies found no differences in RFS and OS between oxaliplatin-and MMC-HIPEC.One study 19  study 20 found no significant differences in RFS and OS for MMC versus oxaliplatin.A large multicentric series from the ASPSM, which included over 500 patients, also showed no differences in OS between oxaliplatin-and MMC-HIPEC 21 .Furthermore, a population-based analysis from the Netherlands found no statistically significant differences in OS, but patients receiving Ox-HIPEC had a 16-month longer OS compared to MMC-HIPEC (46.6 versus 30.7 months) 22 .An Australian series showed a significant survival advantage for patients treated with oxaliplatin compared to MMC-HIPEC (56 versus 29 months) 23 .However, a systematic review concluded that there was insufficient evidence to support either MMC-or Ox-HIPEC due to differences in treatment protocols 4 and some authors have found that the outcomes of pmCRC treated with CRS/HIPEC are independent of the intraperitoneal drug 10 .The present analysis found improved overall survival for patients who received Ox-HIPEC compared to those receiving MMC-HIPEC, with a modest and non-significant difference in RFS.This finding is even more relevant when HIPEC is thought of as a locoregional therapy akin to short-course radiotherapy in rectal cancer, and thus the modest and non-significant differences in RFS are considered.The potential explanation for poor outcomes in patients who received MMC-HIPEC may be due to poor chemosensitivity 3 or prior poor responses to oxaliplatin-based systemic treatment prior to CRS/HIPEC.This is relevant, as preoperative exposure to systemic oxaliplatin may induce genetic alterations and clonal selections to metastatic deposits 24 .Further, patients with mucinous histopathological subtypes who often metastasize to the peritoneum may not respond well to oxaliplatin-based therapies 17,25,26 .Thus, MMC-HIPEC may be a surrogate for patients with worse tumour biology.Equally, patients who received MMC-HIPEC were less likely to receive adjuvant systemic chemotherapy, which was independently associated with improved OS-albeit this exposure needs to be interpreted with caution due to risk of overadjustment bias and 'Table 2 fallacy' 14,27 .However, the lack of detailed information on specific regimens of pre-and postoperative systemic chemotherapy is a drawback of the study.Accordingly, it is difficult to conclude a causal relationship between low-dose MMC-HIPEC and worse patient outcomes considering these factors.Double-agent MMC-HIPEC (with cisplatin or irinotecan) was rarely used and no conclusions can be made concerning this subgroup.
There are further limitations to the present study, including selection bias due to its retrospective nature and non-uniform treatment selection criteria across contributing centres, which may lead to a lack of homogeneity in patient populations.Additionally, there are missing data on important prognostic factors (such as the presence of signet ring cells) and it is possible that the differences in patient outcomes are due to uncaptured patient features.Propensity score matching-while a powerful tool for reducing bias in observational studies-can only correct for known variables.Thus, the present study may only provide guidance for reducing HIPEC regimens to high-dose regimens and for evaluating sample sizes for future trials, and it is scientifically unfounded to draw a simple conclusion about the superiority of oxaliplatin-HIPEC.Furthermore, uncertainty remains over how the effect of HIPEC is to be interpreted in the absence of granular data regarding the exact systemic (pre-and postoperative) chemotherapy regimens that were deployed to patients and thus this represents a further shortcoming of the present study.
Despite this, the MitOxHIPEC study has strengths: it is the largest multicentre comparison of HIPEC regimens in pmCRC patients, with over 2000 patients in the unmatched and over 1300 in the matched analyses.To date, the largest series comprises just over 500 patients 21 .Second, collaborating institutions were part of national or international peritoneal surface oncology collaboratives, which maintained prospective databases, reducing missing data.Third, the study used PSM with a 1:1 ratio and nearest-neighbour matching with random order, ensuring an optimal distribution of scores.Finally, the study performed matching on variables known to influence pmCRC patient selection and prognosis and corrected for residual differences in the final modelling to obtain best estimates of the effect of the different HIPEC regimens 28,29 .The methodology potentially offers treatment effect estimation similar to randomized controlled trials 30 .
While the knowledge-base for the utility of HIPEC in peritoneal metastasized colorectal cancer is ever growing, the current body of evidence can be summarized as follows: CRS + MMC-based HIPEC is superior to no CRS/HIPEC 5,31 ; neoadjuvant oxaliplatin-based systemic therapy with subsequent CRS + mono-oxaliplatin-based HIPEC is not superior to CRS without HIPEC in patients treated with preoperative oxaliplatin-based systemic chemotherapy (PRODIGE 7 9 ); CRS + oxaliplatin may result in better survival than CRS + mitomycin C, particularly if low-dose protocols are used, but if higher-dose MMC regimens are used the outcomes may be equivalent (present study).However, whether CRS + MMC-based HIPEC is better than CRS alone remains unclear and there is no evidence to suggest or refute this treatment regimen, but deploying it to patients remains a leap of faith at present.Thus, with these points above, the present study-while hypothesis generatinghelps inform the discussion in this evolving field of medicine and potentially provides a solid basis for future RCTs.
In conclusion, the MitOxHIPEC study suggests that HIPEC has a clinical effect with a dose-response effect, with the oxaliplatin group showing better 90-day mortality rates and high-dose MMC-HIPEC being a worthy alternative.The oxaliplatin + irinotecan regimen showed enhanced efficacy and is promising for future trials.While the data are exploratory, they can inform clinical choices towards standardization in HIPEC use for colorectal cancer.

Fig. 4
Fig. 4 Impact of varying MMC-and Ox-HIPEC protocols on overall survival and recurrence-free survival (continued on next page)HIPEC, hyperthermic intraperitoneal chemotherapy, MMC, mitomycin C.

b
Matched overall survival stratified by oxaliplatin HIPEC intensity

1 Flowchart of patient data selection and analysis
Patients included for overall survival analysis* n = 2093 All patients included for crude short-and long-term analyses: n = 2093 With mitomycin C n = 849 With oxaliplatin n = 1244 Patients included for matched short-and long-term outcome analysis: n = 1324 With mitomycin C n = 662 With oxaliplatin n = 662 Fig.*Of these, 334 had incomplete data on recurrence.Missing data overlapped in some instances for the same patients, accordingly final number with complete data for analysis was 2093.CRS, cytoreductive surgery; HIPEC, hyperthermic intraperitoneal chemotherapy; PCI, peritoneal cancer index; CC, completeness of cytoreduction.Fisher et al. | 3

Table 1 )
. A trend for lower-dose HIPEC regimens to be used more frequently during the time period of 2001-2009 (23.1%) was